The timing and coordination of the secretion of myriad hormones is necessary for the maintenance of homeostasis and optimal body functioning. Traditionally, endocrinologists have focused on the role of negative feedback mechanisms and neuroendocrine pulse generators as the primary mechanisms regulating the temporal pattern of hormone secretion. However, it is becoming increasingly clear that endogenous timing systems play a crucial role in this regulation. We recently found that cells containing a novel inhibitory peptide, gonadotropin-inhibitory hormone (GnlH), are highly localized in the brains of Syrian hamsters and other rodents, with fibers projecting diffusely from the septum to the caudal hypothalamus. Importantly, our pilot work shows that brain or peripheral injections of GnlH inhibit LH in a dose-dependent manner. Furthermore, the GnlH system projects to gonadotropin-releasing-hormone (GnRH) neurons, permitting direct, inhibitory control of GnRH secretion. Fibers originating in the brain clock located in the suprachiasmatic nucleus (SCN) form close appositions with GnlH cell bodies, providing a potential means of temporal control. Finally, GnlH cells contain estrogen receptors and respond to estradiol stimulation, suggesting that estrogen acts on these cells to regulate steroid negative feedback. Together, these findings indicate that the GnlH system is organized to modulate reproductive function and the hypothalamo-pituitary- gonadal (HPG) axis. The present proposal is designed to further explore the neuroanatomical and functional means by which the GnlH system is integrated with well understood mechanisms of reproductive control of the HPG axis. This proposal will establish the precise means of communication 1) from the endogenous circadian clock to the GnlH system, 2) from the GnlH system to the reproductive axis, and 3) the functional consequences of the interactions between this novel system and the reproductive axis. Disruptions in the timing of hormone secretion have pronounced adverse effects on human health. For example, jet lag and shift work lead to a variety of reproductive disturbances and an increased risk of developing endocrine-responsive tumors. This proposal seeks to understand the neural mechanisms responsible for hormonal timing to help guide the treatment/prevention of these endocrine disorders. [unreadable] [unreadable] [unreadable]